# Epigenetic Drivers of Pulmonary Hypertension: Environment Meets Genome

## TL;DR

This paper explores how epigenetic changes, influenced by environmental factors, contribute to pulmonary hypertension and suggests new ways to treat the disease.

## Contribution

The paper introduces a framework linking environmental exposures to epigenetic changes in pulmonary hypertension, offering new therapeutic approaches.

## Key findings

- Epigenetic changes like DNA methylation and histone modification are linked to pulmonary hypertension.
- Environmental factors such as obesity and cigarette smoke trigger epigenetic reprogramming in the disease.
- Molecular hubs like BMPR2 and TGF-β are central to the epigenetic mechanisms in pulmonary hypertension.

## Abstract

Pulmonary hypertension (PH) is a progressive disease in which the pulmonary arteries thicken and narrow, raising pulmonary vascular resistance (PVR) and eventually straining the right ventricle. Known gene mutations explain only a minority of cases and often do not account for why the disease starts, worsens, or varies so widely between patients. Growing evidence suggests that epigenetic changes, chemical marks on DNA and its packaging that alter how genes are used without changing the DNA sequence, help explain this gap. These changes, including DNA methylation, histone modification, and non-coding RNAs, can be triggered by common exposures and disease states, and they can produce lasting shifts in vascular, immune, and metabolic pathways.

This narrative review synthesizes current data showing how intrinsic stresses (mitochondrial dysfunction, oxidative stress, and cancer-like metabolic reprogramming) interact with extrinsic and often modifiable factors. Obesity, cigarette smoke, asbestos exposure, chronic hypoxia, and systemic inflammation drive PH through epigenetic reprogramming. We highlight major molecular hubs implicated across studies, including bone morphogenetic factor receptor 2 (BMPR2), NOTCH3, endothelin-1 (ET-1), transforming growth factor‑β (TGF-β), interleukin‑6 (IL-6), and CCL5, and we summarize emerging therapeutic approaches aimed at epigenetic regulators and microRNA networks.

This narrative review was not conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and does not constitute a formal systematic review. The information in this review provides a practical framework for clinicians and researchers to improve risk assessments, to employ biomarkers, and to develop therapies that go beyond vasodilation to address upstream drivers of pulmonary arterial remodeling. This framework may also serve as a model for other difficult-to-treat diseases in which incomplete genetic explanations and limited attention to environmental exposures have slowed progress in prevention, early detection, and personalized treatment.